Weijing Zhao

Pro12Ala Polymorphism in the PPARG Gene Contributes to the Development of Diabetic Nephropathy in Chinese Type 2 Diabetic Patients

OBJECTIVE Oxidative stress is a major contributing factor in the development of diabetic nephropathy. Peroxisome proliferator–activated receptor γ heterozygous mice and Pro12Ala polymorphism in PPARG exhibited increased resistance to oxidative stress. Smoking increases the production of reactive oxygen species, which accelerates oxidative stress under hyperglycemia. To determine whether the Pro12Ala polymorphism, alone or in combination with smoking, contributes to the development of diabetic nephropathy, a case-control study was performed in 760 Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Among patients, 532 had diabetic nephropathy with microalbuminuria (n = 245) or overt albuminuria (n = 287), and 228 did not show either of these symptoms but had had diabetes for ≥10 years and were not undergoing antihypertension treatment. RESULTS After adjustment for confounders, the Pro/Pro genotype was significantly associated with diabetic nephropathy (odds ratio 2.30 [95% CI 1.18–4.45], P = 0.014); smoking was also an independent risk factor for diabetic nephropathy (1.99 [1.08–3.68], P = 0.029). In addition, we identified possible synergistic effects; i.e., the high-risk group (smokers with the Pro/Pro genotype) showed 4.52 times higher risk (1.78–11.48, P = 0.002) of diabetic nephropathy than the low-risk group (nonsmokers with the Pro/Ala genotype) in a multiple logistic regression analysis controlled for the confounders. CONCLUSIONS Our results indicated that the Pro/Pro genotype and smoking were significant independent risk factors for diabetic nephropathy. The possible synergistic effects of genotype and smoking may aggravate oxidative stress and contribute to the development of diabetic nephropathy.

A high thyroid stimulating hormone level is associated with diabetic peripheral neuropathy in type 2 diabetes patients.

AIM The association between thyroid stimulating hormone (TSH) and type 2 diabetes mellitus (T2DM) is well known. However, whether TSH is related to diabetic peripheral neuropathy (DPN) has not been studied. The aim of this study was to explore the relationship between TSH and DPN in Chinese patients with T2DM. METHODS In this cross-sectional study, 605 patients with T2DM were enrolled. Subclinical hypothyroidism (SCH) was defined as an elevated TSH level (>4.0mIU/L) and a normal free thyroxine level. DPN was evaluated by neurological symptoms, neurological signs, and electromyogram. RESULTS Serum TSH levels were significantly higher in DPN and signs of DPN compared with non-DPN T2DM patients (both P<0.01).The prevalence of DPN and signs of DPN in SCH subjects was higher than that in euthyroid subjects (both P<0.01). Spearmans correlation analysis showed that the serum TSH level was positively associated with DPN (r=0.172, P<0.01). A significant independent association between TSH and DPN was found by multiple logistic regression analysis after adjusting for potential confounding variables [odds ratio (OR)=1.365, P<0.01]. The patients were sequentially assigned to quartiles according to TSH level. Compared with quartile 1, patients in quartile 2 (P<0.01), quartile 3 (P=0.01), and quartile 4 (P<0.01) had a higher risk of DPN. Receiver-operating characteristic curve analysis revealed that the optimal cutoff point of TSH to indicate DPN was 3.045mIU/L in men and 2.94mIU/L in women. CONCLUSION TSH level is independently associated with DPN in Chinese population with T2DM. A high serum TSH level may be a potential risk factor for DPN.

Development of Multimarker Diagnostic Models from Metabolomics Analysis for Gestational Diabetes Mellitus (GDM)

Although metabolomics are desirable to understand the pathophysiology of gestational diabetes mellitus (GDM), comprehensive metabolomic studies of GDM are rare. We aimed to offer a holistic view of metabolites alteration in GDM patients and investigate the possible multimarker models for GDM diagnosis. Biochemical parameters and perinatal data of 131 GDM cases and 138 controls were collected. Fasting serum samples at 75 g oral glucose tolerance test were used for metabolites by ultra performance liquid chromatography-quadrupole-time of flight-mass spectrometry, ultra performance liquid chromatography-triple triple-quadrupole-mass spectrometry and gas chromatography- time-of- flight mass spectrometry platforms. Significant changes were observed in free fatty acids, bile acids, branched chain amino acids, organic acids, lipids and organooxygen compounds between two groups. In receiver operating characteristic (ROC) analysis, different combinations of candidate biomarkers and metabolites in multimarker models achieved satisfactory discriminative abilities for GDM, with the values of area under the curve (AUC) ranging from 0.721 to 0.751. Model consisting of body mass index (BMI), retinol binding protein 4 (RBP4), n-acetylaspartic acid and C16:1 (cis-7) manifested the best discrimination [AUC 0.751 (95% CI: 0.693–0.809), p < 0.001], followed by model consisting of BMI, Cystatin C, acetylaspartic acid and 6,7-diketoLCA [AUC 0.749 (95% CI: 0.691–0.808), p < 0.001]. Metabolites alteration reflected disorders of glucose metabolism, lipid metabolism, amino acid metabolism, bile acid metabolism as well as intestinal flora metabolism in GDM state. Multivariate models combining clinical markers and metabolites have the potential to differentiate GDM subjects from healthy controls.

Insights into pathogenesis of five novel GCK mutations identified in Chinese MODY patients

OBJECTIVE Heterozygous inactivating mutations in GCK are associated with defects in pancreatic insulin secretion and/or hepatic glycogen synthesis leading to mild chronic hyperglycaemia of maturity onset diabetes of young type 2 (MODY2). However, the effect of naturally occurring GCK mutations on the pathogenesis for MODY2 hyperglycaemia remains largely unclear, especially in the Asian population. The aim of this study is to explore the potential pathogenicity of novel GCK mutations related to MODY2. METHODS Genetic screening for GCK mutations from 96 classical MODY families was performed, and structure-function characterization and clinical profile of identified GCK mutations were conducted. RESULTS Five novel (F195S, I211T, V222D, E236G and K458R) and five known (T49N, I159V, R186X, A188T and M381T) mutations were identified and co-segregated with hyperglycaemia in their pedigrees. R186X generates non-functional truncated form and V222D and E236G fully inactivate glucokinase due to severe structure disruptions. The other seven GCK mutations exhibited marked reductions in catalytic efficiency and thermo-stability; notably, the interaction with GKRP was significantly enhanced in I211T, I159V, T49N and K458R, reduced in F195S and M381T, and completely lost with A188T. 31% (17/55) of MODY2 patients showed signs of insulin resistance. Conventional hypoglycaemia treatment did not improve the HbA1C in MODY2 patients when insulin resistance is not present. CONCLUSIONS Five novel GCK mutations have been identified in Chinese MODY. The defects in enzymatic activity and protein stability, together with alteration of GKRP binding on GCK mutants may synergistically contribute to the development of MODY2 hyperglycaemia. No treatment should be prescribed to MODY2 patients when insulin resistance is not present.

Early elevated alkaline phosphatase increases the risk of large-for-gestational-age birth weight in pregnant women with normal glucose tolerance

AIMS The aim of this study was to assess the association between levels of alkaline phosphatase (ALP) in early pregnancy and the incidence of large-for-gestational-age (LGA) neonates in pregnant women without gestational diabetes mellitus. METHODS A prospective cohort was carried out in 544 women and their biochemical parameters including serum ALP and demographic characteristics were collected in 13-16th gestational week. At 24-28th weeks of gestation, 50 g oral glucose challenge test and oral 75 g glucose tolerance test was performed. LGA was defined as birth weight ≥ 90th percentile for completed week of gestational age based on the sex-specific growth curves. Logistic regression and receiver operating characteristic analysis were utilized to identify independent risk factors and odds ratio among ALP quartiles for incidence of LGA. RESULTS Women diagnosed as LGA held higher level of ALP than women in non-LGA group (P = 0.008). Moreover, ALP (odds ratio (OR) 1.05 [95% confidence interval (CI): 1.00, 1.10]) was the independent risk factors associated with LGA. Compared with ALP quartile 1, women in quartile 4 had more than 2.5-fold increased odds of LGA (OR 3.78, 95% CI: 1.10, 13.02), and the risk reached 4 times after adjusting several covariates (OR 4.15, 95% CI: 1.14,15.13). CONCLUSIONS A significantly increased risk of LGA was associated with higher serum concentrations of ALP in pregnant women with NGT, even it is in normal reference range.

Elevated First-Trimester Total Bile Acid is Associated with the Risk of Subsequent Gestational Diabetes.

The aim of the current study is to assess whether total bile acid (TBA) level in first trimester pregnancy is associated with gestational diabetes mellitus (GDM). Biochemical parameters including serum TBA of 742 pregnant women were collected within 12 weeks of gestation and compared. At 24–28th weeks of gestation, 75 g oral glucose tolerance test (OGTT) was performed. The perinatal data of 330 women were collected. The results demonstrated women with GDM (n = 268) had higher first-trimester serum levels of TBA compared with healthy subjects (n = 474) (2.3 ± 1.4 μmol/L vs. 1.9 ± 1.0 μmol/L, P < 0.001). TBA was independently associated with GDM [adjusted odds ratio (AOR), 1.38; 95% confidence interval (CI), 1.18–1.61, P < 0.001]. Compared to the first category of TBA, women in the highest category had a marked increase in risk for GDM (AOR, 7.72; 95% CI, 3.22–18.50, P < 0.001). In conclusion, higher first-trimester TBA levels, even within normal range, may help indicate increased risk of GDM.